Transplantation of donor tissue into a recipient can be used to treat a wide variety of disorders, including heart disease, neoplastic disease, and endocrine disease. The clinical application of transplantation-based therapies are, however, limited by several factors. These factors include immune rejection of transplanted allogeneic or xenogeneic tissue by the transplant recipient, a shortage of allogeneic donor-tissue, and donor-propagated immune attack of recipient tissue (graft-versus-host-disease).
Immune rejection of transplanted donor-tissue can be the most serious barrier to more widespread availability of the benefits of transplantation-based therapies. Implantation of allogeneic or xenogeneic donor-tissue into an immunocompetent recipient generally results in a vigorous and destructive immune response directed against the donor-graft. Efforts to prevent immune-based destruction of donor tissue have generally fallen into two categories. In one approach, efforts have been directed to moderating the recipient's immune response, e.g., by the induction of specific immunological tolerance to transplanted tissue, or much more frequently, by the administration of broad-spectrum immune suppressants, e.g., cyclosporin. In the other major approach, efforts to prolong the acceptance of a donor-graft have been directed to rendering the donor-graft less susceptible to attack, e.g., by immunoisolating the donor-tissue by encapsulating it in a way which minimizes contact of elements of the recipient's immune system with the encapsulated donor tissue.
Immunoisolation is particularly attractive for the treatment of endocrine disorders or in hormone or enzyme replacement therapies. For example, the implantation of immunoisolated pancreatic islet cells can be used to restore glucose-responsive insulin function in a diabetic recipient. Islets can be placed in a mechanical enclosure, or can be coated with a material, which allows relatively free diffusion of glucose, insulin, nutrients, and cellular waste products but which is impervious to components of the recipient's immune system.
A microcapsule typically includes an inner core in which living cells are embedded and optionally an outer semipermeable coating. The outer coating often has a porosity which prevents components of the implant recipient's immune system from entering and destroying the cells within the microcapsule. Gel microcapsules containing a small number of living cells have been used to transplant both allogeneic and xenogeneic donor cells into recipient animals. Several methods for microencapsulating cells, e.g., pancreatic islet cells, in an alginate gel have been investigated. These include the alginate-polylysine technique described in Lim et al., U.S. Pat. No. 4,391,909 and Soon-Shiong et al., Transplantation, 54:769-774 (1992), the alginate-chitosan system described in Rha et al., U.S. Pat. No. 4,744,933, and the polyacrylate encapsulation method described in Sefton, U.S. Pat. No. 4,353,888. A tissue response to implanted microcapsules limits the usefulness of this class of therapeutic entities. The fibrotic response consists of host deposition of fibrous proteins that causes death and rejection of the encapsulated therapeutic substance. Immunosuppressive drugs have been used to delay rejection, for example, fetal nigral allograft survival and function has been shown for up to 10 months after transplantation and immunosuppression (with the agents cyclosporin, azathioprine, and prednisone) in a human Parkinson's patient. (Widner et al., (1991) Transplant. Proc., 23:793). Function of islet cells implanted in polyalginate microcapsules was extended for a period approximately 4-fold that of the control by administration of cyclosporin A (CsA, 20-30 milligrams/kg/day, s.c.; Langa, Ed. R.G. Landes, Press 1994, Texas, Immunomodulation of Pancreatic Islets). However, a variety of negative side effects of CsA include nephrotoxicity, increased incidence of viral diseases, and transient liver dysfunction. Drugs that are safe, economical, and convenient for suppression of fibrotic rejection of implanted devices are clearly needed.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those herein can be used in the practice or testing of the present invention, the preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.